Comparison of permeation mechanisms in sodium-selective ion channels

Abstract

Voltage-gated sodium channels are the molecular components of electrical signaling in the body, yet the molecular origins of Na⁺-selective transport remain obscured by diverse protein chemistries within this family of ion channels. In particular, bacterial and mammalian sodium channels are known to exhibit similar relative ion permeabilities for Na⁺ over K⁺ ions, despite their distinct signature EEEE and DEKA sequences. Atomic-level molecular dynamics simulations using high-resolution bacterial channel structures and mammalian channel models have begun to describe how these sequences lead to analogous high field strength ion binding sites that drive Na⁺ conduction. Similar complexes have also been identified in unrelated acid sensing ion channels involving glutamate and aspartate side chains that control their selectivity. These studies suggest the possibility of a common origin for Na⁺ selective binding and transport.

Keywords: Acid sensing ion channel; Ion permeation; Ion selectivity; Molecular dynamics simulation; Voltage-gated sodium channel.

Figure 1:

The structure of Na_v channels. Main structural elements of the bacterial channel Na_vAb showing the arrangment of segments S1 to S6 forming the pore domain (PD) and the volatge-sensing domain (VSD). For clarity, the segments forming the PD of one subunit and the VSD of another have been omitted. In the VSD, the key arginines playing a role in gating are represented as pink sticks and labelled. More detailed representations of the SFs are added as inserts (colored sticks, C in cyan and gray for back subunit, N in blue and O in red, 3 subunits shown), displaying Na_vAb (top center), with its specific sequence of residues TLES and the 3 binding sites for Na⁺ S_HFS, S_CEN and S_IN as red dashed circles, and Na_vPaS (top right), with the key residues of the DEKA locus indicated (D, E, and K, the subunit carrying A, DIV, is not shown), as well as the extracellular ring of charged residues (E and E, as DIII doesn’t carry a charged residue in Na_vPaS), the name of each domain DI, DII and DIII is indicated. To the left a sequence alignment of Na_vBaCs (Na_vAb and Na_vRh) and human Na_v1.2 is shown. Bold and highlighted letters indicate key DEKA and EEEE rings, as well as the vestibular EEDD ring.

Figure 2:

Conduction of sodium in Na_vAb. 2D free energy projection for Na⁺ ions when 3 ions occupy the filter, with Na⁺-Na⁺ corresponding to the center of mass position of the two upper ions. The lowest free energy pathway is via knock-on conduction, indicated with a solid red curve, with pass-by conduction indicated with a dashed curve. Illustrations are schematic and based on free energy results presented in (Boiteux et al., 2014a), with contouring at 0.5 kcal/mol.

Figure 3:

Ion conduction in model human Na_v1.2 for Na⁺ (A) and K⁺ (B). Insets show configurations during conduction. A) Two ion occupancy dominates for Na⁺. As the ions enter the SF they bind to carboxylates and create multi-ion/multi carboxylate complexes. Lysine creates a stable state with Na⁺ in the S_HFS to allow pass-by conduction (solid red curve). When lysine is in the lower pore no conduction is observed (dashed curve). B) The K⁺ ion singly binds to the carboxylates and waits for lysine to undergo structural isomerization to pass lysine in the lower SF (solid red curve). Illustrations are schematic and based on free energy maps presented in (Flood et al., 2018), with contouring at 0.5 kcal/mol.

Figure 4:

Free energy profile for Na⁺ (orange) and K⁺ (purple) in ASIC PDB:4NTW (A) and PDB:2QTS (B), based on data presented in (Lynagh et al., 2017). Insets show Na⁺ and K⁺ in key sites and labels indicate the residues that the respective ions are binding to.